Littlejohn Alison F, Tucker Steven J, Mohamed Ahmed A A, McKay Stephen, Helms Matt J, Vandenabeele Peter, MacEwan David J
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland AB25 2ZD, UK.
Biochem Pharmacol. 2003 Jan 1;65(1):91-9. doi: 10.1016/s0006-2952(02)01443-0.
Tumour necrosis factor-alpha (TNF) is capable of activating many downstream signaling molecules via its two receptors TNFR1 and TNFR2. TNF can stimulate the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) as well as the stress induced kinase c-Jun N-terminal kinase (JNK) through mechanisms that are not fully delineated. NF-kappaB becomes activated mainly through TNFR1 while JNK can be stimulated by either TNF receptor subtype. TNF can also induce apoptosis within cells due to its ability to recruit procaspase-8 to TNFR1, which in turn induces the caspase proteolytic cascade. We provide evidence here in human cells, that TNF-induced JNK activation is under the influence of caspases while NF-kappaB activity is not. By using pharmacological inhibitors of caspases, we have shown that JNK activity is reduced following caspase inhibition, especially when caspase-3 is targeted. NF-kappaB activity, as assessed by IkappaBalpha or IkappaBbeta degradation, electrophoretic mobility shift assay and NF-kappaB gene reporter assays, is shown to be unaffected by caspase inhibition. Therefore, downstream TNF receptor signaling events are differentially influenced by caspases.
肿瘤坏死因子-α（TNF）能够通过其两种受体TNFR1和TNFR2激活许多下游信号分子。TNF可通过尚未完全阐明的机制刺激促炎转录因子核因子-κB（NF-κB）以及应激诱导激酶c-Jun氨基末端激酶（JNK）。NF-κB主要通过TNFR1激活，而JNK可被任一TNF受体亚型刺激。TNF还可因其将procaspase-8募集至TNFR1的能力而诱导细胞凋亡，进而诱导半胱天冬酶蛋白水解级联反应。我们在此提供人类细胞中的证据，表明TNF诱导的JNK激活受半胱天冬酶影响，而NF-κB活性则不受其影响。通过使用半胱天冬酶的药理学抑制剂，我们发现半胱天冬酶抑制后JNK活性降低，尤其是靶向半胱天冬酶-3时。通过IkappaBalpha或IkappaBbeta降解、电泳迁移率变动分析和NF-κB基因报告分析评估的NF-κB活性显示不受半胱天冬酶抑制的影响。因此，下游TNF受体信号事件受半胱天冬酶的影响存在差异。
